Three myths about Plasmalyte, Normosol, and LR

Introduction: Selecting the best balanced crystalloid

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About six months ago, Genius General Hospital added Normosol to its formulary.For those of you not familiar with Normosol, it is produced by Hospira and is essentially a generic version of Plasmalyte by Baxter (table below).Although most evidence has been obtained with Plasmalyte, this is applicable to Normosol as well.

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Which balanced crystalloid is better, LR or Plasmalyte?Unfortunately there is surprisingly little clinical evidence to base this selection on.Nonetheless, it may be helpful to debunk a few common myths about these solutions.

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MYTH #1: Plasmalyte is significantly more alkalinizing than LR.

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The predicted effect of crystalloids on blood acid-base status depends on their strong ion difference (SID).If you prefer to conceptualize pH using the Henderson-Hasselbach model, then you can think about SID in this context as equal to “bicarbonate equivalents” (e.g., LR contains 28 mM of lactate, which promptly generates 28 mM of bicarbonate in the body, and has a SID of 28 mM).Assuming the patient starts out at a normal acid-base status, a fluid with a SID of 24 mM should have no effect on pH status, a fluid with SID below 24 mM should cause a hyperchloremic acidosis, and a fluid with SID above 24 mM should cause a metabolic alkalosis:

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Predicted effect of infusing various crystalloids into a hypothetical 70-kg patient on standard base excess (SBE).It is predicted that Plasmalyte and NS have equal and nearly opposite effects on the SBE (Omron 2009).

Therefore it is widely believed that there is a significant difference between the way these three fluids affect pH as shown above, with LR being about half-way between NS (an acidifying fluid) and Plasmalyte (an alkalinizing fluid).However, this is not what is observed in animal or human studies.For example, Noritomi 2011and Traverso 1986evaluated the effect of NS, LR, and Plasmalyte resuscitation in porcine and dog models of hemorrhagic shock (figures below).In both cases there was a significant pH difference between NS and LR, but surprisingly no difference between LR and Plasmalyte:

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Three prospective RCTs have been performed comparing LR and Plasmalyte for intraoperative resuscitation during renal transplant and hepatic resection (Shin 2011, Hadimioglu 2008, Weinberg 2014).Two of these found no difference in base excess, while Shin 2011did find Plasmalyte to be slightly more alkalinizing than LR.For example, data from Hadimioglu shown below illustrates the standard base excess following renal transplantation with intraoperative resuscitation using NS, LR, or Plasmalyte.Note again a clear difference between NS and LR, but no difference between LR and Plasmalyte:

Chowdhury 2012 found that infusion of two liters plasmalyte into normal volunteers decreased the average serum SID from 43 mM to 40 mM.These authors noted that since plasmalyte has a SID of 49 mM, it would be expected to have the oppositeeffect (i.e., draw the serum SID upwards towards 49 mM).Thus again it seems that Plasmalyte is not as alkalinizing as predicted.

Truth: Plasmalyte doesn't have the predicted pH effect because of failure to metabolize gluconate.

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The alkalinizing effect of Plasmalyte is due to a combination of sodium acetate and sodium gluconate.It is widely believed that these anions are rapidly metabolized by the body, each yielding bicarbonate (1).This is what the product information about Plasmalyte from Baxterreports.Thus, the gluconate and acetate may be conceptualized as forms of “potential bicarbonate” similar to sodium lactate in LR (2).

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Plasmalyte's failure to alkalinize suggests a problem with acetate or gluconate.Based on data using Ringer's Acetate, acetate can alkalinize quite effectively.Therefore the problem lies with sodium gluconate.Hospira actually admits in the package insert for Normosol that “although gluconate is a theoretical alternate metabolic source of bicarbonate anion, a significant anti-acidotic action has not been established.”

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Surprisingly little is known about human metabolism of sodium gluconate (discussed in the deranged physiology blog).It appears that the majority of gluconate is actually excreted unchanged in the urine (60-85% according to an industrial toxicology report).

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Of course, if the gluconate is not metabolized then it will never generate “potential bicarbonate” and thus will have no effect on pH.This is exactly what was found by Naylor 1986 and Muller 2012 in two studies of resuscitation of diarrheic calves, and Kirkendol 1980 in a study of dogs (figures below).Infused sodium gluconate failed to cause any change in acid-base status.

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Bottom line?Plasmalyte may be slightly more alkalinizing than LR, due to metabolism of a small fraction of infused sodium gluconate.However, any difference is probably not clinically significant.

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Gluconate excreted in the urine may act as an osmotic diuretic

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It appears that sodium gluconate is mainly being excreted unchanged in the urine.Any hydrophilic substance given intravenously in significant quantities and excreted unchanged could potentially act as an osmotic diuretic.There is some evidence that this is the case.

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Around the 1950s it was noted in multiple studies that calcium gluconate could be used clinically as a diuretic (Dingman 1960).This led to a series of experiments investigating the physiology of calcium gluconate.In 1959, Howard noted in a dog model that calcium gluconate impaired renal sodium reabsorption substantially more than calcium chloride.They hypothesized that gluconate might be causing an osmotic diuretic effect, and subsequently confirmed this by infusing sodium gluconate.In 1971, DiBona confirmed in rats that sodium gluconate has an osmotic diuretic effect.

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Little information exists about the renal handling of gluconate by humans.The majority of sodium gluconate is excreted unchanged in the urine, and this seems to occur rapidly.Following administration intraoperatively, serum gluconate concentrations fall rapidly (Davies 2011).

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If sodium gluconate does have an osmotic diuretic effect, it is probably modest.One liter of Plasmalyte contains 23 mM of sodium gluconate.Estimating that 75% of this is excreted by the kidney and that the urine osmolality of a stressed patient might range between 200-1200 mOsm, this would generate 29-173 ml of urine.This isn't a lot of urine, but it could artificially elevate the measured urine output and thus falsely reassure the clinician that renal perfusion was adequate.

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Investigators have indeed found that compared to NS, patients treated with Plasmalyte urinate sooner and produce more urine (Chowdhury 2012).This has previously been attributed to avoidance of hyperchloremic metabolic acidosis by using Plasmalyte.However, it is also possible that a direct diuretic effect of gluconate could contribute to this.Similarly, it is conceivable that gluconate could increase renal perfusion in a fashion similar to mannitol (an osmotic diuretic, Bragadottir 2012).

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MYTH #3: The lactate in LR may accumulate and cause a dangerous lactic acidosis.

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LR is sometimes avoided because of fear that it could lead to a lactic acidosis or lactate accumulation.This fear is almost always unfounded.First of all, LR contains sodiumlactate (not lactic acid), which is quite simply not an acid:

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More importantly, even if sodium lactate does accumulate a bit, this is probably a good thing.The heart and brain are evolutionarily designed to utilize lactate as a bioenergetic fuel in ischemic conditions (Ichai 2014).Our ancestors developed lactic acidosis when outrunning bears, and evolution has developed ways to utilize this lactate to our advantage.Although we are accustomed to thinking about an elevated lactate level as a bad thing, in reality the lactate itself is not the problem.Recently, Nalos 2014 infused a concentrated sodium lactate solution into heart failure patients, which improved their cardiac function.

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Therefore, the problem of lactate accumulation may be primarily a cosmetic issue.With the exception of patients in frank hepatic failure, LR is unlikely to raise the lactate more than a few mM.The only real issue with this is that clinicians may misinterpret this rise in lactate levels.Current trends in sepsis management are moving away from using lactate as a resuscitation target, so these minor perturbations in lactate may be even less significant in the future (Marik 2013).

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Conclusions

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Plasmalyte and Normosol contain sodium acetate and sodium gluconate as their organic anions, with the common belief that these are promptly metabolized yielding bicarbonate.Unfortunately, the sodium gluconate does not appear to function the way it was intended to.Rather than being metabolized with production of bicarbonate, most of the sodium gluconate is excreted unchanged in the kidneys.It could even have a mild osmotic diuretic effect.

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Existing evidence about Plasmalyte is promising, including a prospective RCT which showed reduced post-operative complications as well as a rat sepsis model showing improved survival and renal function (Zhou 2014, Weinberg 2014).Unfortunately in order to fully understand these studies, we need a better appreciation of the effects of sodium gluconate and sodium acetate.

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LR is simpler and better understood. LR is sometimes avoided due to concerns about lactic acidosis, hyponatremia, or hyperkalemia.However, unless the patient has profound liver failure, accumulation of lactate is minimal and potentially beneficial.The myth that hyperkalemia is a contraindication to LR was debunked previously.Concerns about the hypotonicity of LR are likely exaggerated (LR has an osmolarity of 274 mOsm, very close to the normal range of 275-295 mOsm).Thus, for the vast majority of critically ill patients, LR is a physiologic and safe fluid choice.

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In summary, existing evidence indicates that Plasmalyte and LR are both superior to NS.It is less clear how Plasmalyte compares to LR.The choice of sodium gluconate and acetate as the alkali in Plasmalyte may be a mistake.Sodium gluconate is not metabolized well, and there is a question of potential toxicity with sodium acetate (Davies 2011).Given that sodium lactate is more physiologic and potentially beneficial, this might tip the balance in favor of using LR for now.Further evidence is needed.

Notes

(1) I have previously made this statement in the blog, most notably in the blog on DKA.Therefore, in this blog post I'm myth-busting myself.I have revised DKA post accordingly (see footnote #2). Please accept my apologies.

(2) I apologize if I'm shifting back and forth between Henderson/Hasselbach and Stewart's terminologies.Ultimately these models are not mutually exclusive, but rather different ways of describing the same phenomenon.

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Comment Here

I really love this post! Thank you for applying the Stewart approach, and for helping to debunk the myth about Ringer’s lactate and lactic acidosis.

Best wishes,

D Perera (Intern, Australia)

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3 years ago

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Michael Liu, Pharm.D., BCCCP, BCNSP, BCPS

The SPLIT Trial in JAMA Oct 2015 is a high QOE study that evaluated multiple clinical outcomes as opposed to laboratory markers, which were done with most studies, on Plasmalyte vs. NS. Overall, it suggest that the acid-base benefits of plasmalyte doesn’t necessarily translate to clinical benefits

My question is, although LR is a better choice than 0.9% NaCl in avoiding causing acidosis.
In the situation of large volume fluid administration to a normovolemic (or near normal) patient (i.e. one under general anesthesia with minimal fluid losses), does large volume LR infusion cause a hyperchloremic metabolic acidosis?

Thanks!
Ben

What's Your Job?

Doctor

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1 year ago

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Dan

Thank you for the interesting post. Good read. I did laugh however at the mention of evolution. I clicked the reference link and found no evidence of evolution. Nor did I find anything about our ancestors running from bears. The information about IV solutions was quite helpful however.

What's Your Job?

RN EMT-P

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9 months ago

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Hans Bahlmann

Hi. Great post, espec. about glucagon. . Two comments though: 1. As I understand it lactate is a strong ion, thus the lactate in RL and the lactate accumulating in e,g anoxia are the same ions (fully dissociated), they cause acidosis by decreasing SID. The difference is that in RL the lactate is accompanies by sodium,a strong cation, increasing SID, while in lactic acidosis it is accompanies by hydrogen, a weak cation, with no effect on SID
2. The potential alkalinizing effect of acetate and gluconate is not about that they can be converted to bicarbonate, it is about that they can be converted (from being strong anions) to a weak anion (which happens to be bicarbonate but that is not essential), thus increasing SID.